Charcot-Marie-Tooth disease (CMT) is a common peripheral neuropathy with different modes of inheritance and extensive genetic heterogeneity. Significant progress has been made in the elucidation of the molecular defects of autosomal dominant forms leading to the identification of several peripheral nerve proteins (PMP-22, PO, and Connexin 32). The goal of this proposal is to employ similar positional cloning techniques to identify the defects for two different forms of autosomal recessive CMT (CMT4B and C). We have previously collected a large series of CMT4 families and proposed an improved classification into three types A, B, and C. In addition, we demonstrated linkage of one group: CM4A to chromosome 8q21. Subsequently, we have shown that CMT4B and CMT4C do not map to this chromosomal region. Large inbred CMT4B and CMT4C families will be genotyped for chromosomal localization using linkage analysis. Once a linkage is detected, a YAC and a PAC contig will be initiated across the region. Using the contig, we will generate additional repeat markers in the region. Key recombination events and linkage disequilibrium will be investigated to further narrow the disease flaking interval. The Direct selection technique will subsequently be used to construct a transcription map in the region allowing for candidate genes to be tested for mutations.